Homer 1a uncouples metabotropic glutamate receptor 5 from postsynaptic effectors

Abstract

Metabotropic glutamate receptors (mGluRs) and Homer proteins play critical roles in neuronal functions including plasticity, nociception, epilepsy, and drug addiction. Furthermore, Homer proteins regulate mGluR1/5 function by acting as adapters and facilitating coupling to effectors such as the inositol triphosphate receptor. However, although Homer proteins and their interaction with mGluRs have been the subject of intense study, direct measurements of Homer-induced changes in postsynaptic mGluReffector coupling have not been reported. This question was addressed here by examining glutamatergic excitatory postsynaptic currents (EPSCs) in rat autaptic hippocampal cultures. In most neurons, the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine strongly inhibited the EPSC acutely. This modulation occurred postsynaptically, was mediated primarily by mGluR5, and was inositol triphosphate receptor-dependent. Expression of the dominant negative, immediate early form of Homer, Homer 1a, strongly reduced EPSC modulation, but the W24A mutant of Homer 1a, which cannot bind mGluRs, had no effect. (S)-3,5-dihydroxyphenylglycine-mediated intracellular calcium responses in the processes of Homer 1a-expressing neurons were reduced compared with those in Homer 1a W24A-expressing cells. However, neither the distribution of mGluR5 nor the modulation of somatic calcium channels was altered by Homer 1a expression. These data demonstrate that Homer 1a can reduce mGluR5 coupling to postsynaptic effectors without relying on large changes in the subcellular distribution of the receptor. Thus, alteration of mGluR signaling by changes in Homer protein expression may represent a viable mechanism for fine-tuning synaptic strength in neurons.autapse ͉ calcium channel ͉ excitatory postsynaptic current ͉ hippocampal M etabotropic glutamate receptors (mGluRs) are class 3 G protein-coupled receptors expressed throughout the brain. Group I mGluRs 1 and 5 couple to the phospholipase C/calcium release cascade and to pathways regulating ion channels and synaptic currents (1, 2). In the brain, group I mGluRs are often expressed postsynaptically, where they regulate NMDA and AMPA receptor function and mediate multiple forms of plasticity (3).The Homer family of postsynaptic scaffolding proteins was discovered by the regulated expression of the member subsequently termed Homer 1a (4). Levels of Homer 1a and variant Ania-3 are increased after periods of activity or stress, injury, or novel experience (4, 5). Other ''long'' Homer proteins (1b, 1c, 2, and 3) are expressed constitutively (6-8) and, unlike Homer 1a, form clusters mediated by their long C termini. Homer proteins organize postsynaptic proteins around the active site (7) by binding several targets including group I mGluRs, inositol triphosphate receptors (IP 3 Rs), Shank, and the TRPC1 cation channel (9-12).Homer proteins also influence the function of their binding partners. Binding to Homers can alter the function of TRPC1 (12), and group I mGluRs couple more strongly to some effectors (...

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

“…We also found that the mGlu5-Homer interaction was reduced in wildtype animals after DHPG treatment (P , 0.05, unpaired t test). This is in accordance with sequestration of mGlu1/5 by Homer1a, which is translated locally in an activity-driven manner after DHPG treatment, thereby reducing the interaction of the long forms of Homer with mGlu1/5 (Kammermeier et al, 2000;Kammermeier and Worley, 2007). However, it should be noted that others have reported an increase in mGlu5-Homer interaction after DHPG treatment (Rong et al, 2003;Hu et al, 2012).…”

Phosphorylation of Homer3 by Calcium/Calmodulin-Dependent Kinase II Regulates a Coupling State of Its Target Molecules in Purkinje Cells

“…The inducible short form of Homer1, Homer1a, is postulated to function as an intrinsic dominant negative by uncoupling between Homer-mediated target molecules (Kammermeier and Worley, 2007). In the present study, we demonstrated another mechanism for uncoupling of Homer target molecules by phosphorylation.…”

“…The long-form Homer proteins, Homer1b/c, Homer2, and Homer3, have the C-terminal coiledcoil region, which is responsible for their tetramer formation and enable to link target molecules at specific cellular regions, such as at excitatory postsynaptic sites (Hayashi et al, 2006). In contrast, Homer1a, which shows synaptic activity-dependent expression and fails to form tetramer attributable to lacking a coiled-coil region, is thought to function as a natural dominant negative to break clustering and/or linking target molecules (Brakeman et al, 1997;Kato et al, 1998;Kammermeier and Worley, 2007).…”

Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

“…The continuous presence of Homer1a may therefore profoundly change neuronal signaling pathways that may in turn render the organism more vulnerable to chronic stress. In addition, it has previously been shown that interactions between NMDA and mGluR5 receptors are mediated by the PSD95/ Shank/Homer1 complex (Hayashi et al, 2009;Bertaso et al, 2010), and Homer1a was demonstrated to be a key modulator of mGluR5 coupling to effector targets that produce excitatory postsynaptic currents (Kammermeier and Worley, 2007). Given the increasing body of evidence showing that NMDA receptor targeting agents produce rapid-acting antidepressant effects (Krystal et al, 2013;Kavalali and Monteggia, 2012), a Homer1a-mediated overactivation of this signaling pathway may profoundly affect antidepressant treatment efficacy.…”